This application is a 371 of PCT/JP00/06014 filed Sep. 5, 2000.
The present invention relates to a prophylactic and therapeutic medicament for ophthalmic diseases having a leukocyte (neutrophil)-derived elastase inhibitory activity.
JP-B 5-81586 and JP-A 5-194366 (corresponding to EP-A 539223) disclose a compound represented by the formula (I): 
(hereinafter referred to as a compound of Formula (I)) and a salt or hydrate thereof, which has a human neutrophil-derived elastase inhibitory activity and is effective for preventing and treating diseases such as pulmonary emphysema, atherosclerosis and rheumatoid arthritis.
On the other hand, the ophthalmologic field also involves various diseases relating to leukocytes and their elastases. For example, ophthalmic infections, corneal traumas, corneal ulcers and uveitis may be mentioned in an ophthalmic infection, the cellular infiltration of leukocytes results in an intraocular abscess [Invest. Ophthalmol. Vis. Sci., 40, 385-391 (1999)]. An alkaline trauma (erosion) which is one of corneal traumas allows leukocytes to, be infiltrated into corneal stromal cells at an early stage of the alkaline erosion, two to three weeks after which the elevation of leukocyte elastase activity is observed [Ophthalmic. Res., 29, 154-160 (1997)]. Also in a case of corneal ulcers, a corneal wound or detachment results in the infiltration of leukocytes into a corneal stroma, which leads to the release or secretion of a protease such as an elastase or collagen [Klin. Monatsbl. Augenheilkd, 188, 593-595 (1986)]. An uveitis, especially Behcet""s disease, was reported to undergo an increase in a plasma leukocyte elastase [Clin. Chim. Acta 236:129-134 (1995), Acta, Ophthalmol. Scand. 75:287-289 (1997), J.Reumatol. 25: 326-328 (1998)]. While leukocytes or their elastases were reported to be involved in the ophthalmic diseases mentioned above, no actual effect of the administration of an elastase inhibitor was reported.
While in JP-A 5-221872 (corresponding to EP-A 519354) and JP-A 6-509232 (corresponding to EP-A 596118), a microbe-derived substance having human leukocyte elastase inhibitory activity is described generally to be useful as a prophylactic and therapeutic medicament against a corneal scar tissue formation or a fibroblast proliferation [eye solidification (burn, mechanical or chemical damage, keratoconjunctivitis) and the like], it was not administered actually to verify its effect, and is different totally from a compound of Formula (I).
An objective of the present invention is to develop a prophylactic and therapeutic medicament for ophthalmic diseases containing as an active ingredient a compound of Formula (I).